This invention relates to substituted 2-anilinopyrimidines, to processes for their preparation, to pharmaceutical compositions containing them, and to their use in medicine.
Protein kinases participate in the signalling events which control the activation, growth and differentiation of cells in response to extracellular mediators and to changes in the environment. In general, these kinases fall into two groups; those which preferentially phosphorylate serine and/or threonine residues and those which preferentially phosphorylate tyrosine residues [Hanks, S K, Hunter T, FASEB. J. 9, 576-596 (1995)]. The serine/threonine kinases include for example, protein kinase C isoforms [Newton A C, J. Biol. Chem. 270, 28495-28498 (1995)] and a group of cyclin-dependent kinases such as cdc2 [Pines J, Trends in Biochemical Sciences 18, 195-197 (1995)]. The tyrosine kinases include membrane-spanning growth factor receptors such as the epidermal growth factor receptor [Iwashita S and Kobayashi M. Cellular Signalling 4, 123-132 (1992)], and cytosolic non-receptor kinases such as ZAP-70 and csk kinases [Chan C et al Ann. Rev. Immunol. 12, 555-592 (1994)]. A particular group of non-receptor tyrosine kinases are a group known as the src family which includes p56lck and p59fyn [Kefelas P et al International Journal of Biochemistry and Cell Biology 27, 551-563 (1995)].
Inappropriately high protein kinase activity has been implicated in many diseases resulting from abnormal cellular function. This might arise either directly or indirectly, for example by failure of the proper control mechanisms for the kinase, related for example to mutation, over-expression or inappropriate activation of the enzyme; or by over- or underproduction of cytokines or growth factors also participating in the transduction of signal upstream or downstream of the kinase. In all of these instances, selective inhibition of the action of the kinase might be expected to have a beneficial effect.
We have now found a series of substituted 2-anilinopyrimidines which are potent and selective inhibitors of protein kinases, especially src-family protein kinases. The compounds are thus of use in the prophylaxis and treatment of immune diseases, hyperproliferative disorders and other diseases in which inappropriate protein kinase action is believed to have a role.
Thus, according to one aspect of the invention, we provide a compound of formula (1): 
wherein R1 is a xe2x80x94XR8 group [where X is a covalent bond, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94C(S)xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94S(O2)xe2x80x94, xe2x80x94CH2xe2x80x94, -or N(R9)xe2x80x94 [where R9 is a hydrogen atom or a straight or branched alkyl group] and R8 is a hydrogen atom or an optionally substituted aliphatic, cycloaliphatic, heteroaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group], or a xe2x80x94NO2, xe2x80x94CN, xe2x80x94SO2NH2, xe2x80x94SO2NHR8, xe2x80x94SO2N(R8)2 [where each R8 group may be the same or different], xe2x80x94CONH2, xe2x80x94CONHR8, xe2x80x94CON(R8)2 [where each R8 group may be the same or different], xe2x80x94CSNH2, xe2x80x94CSNHR8, xe2x80x94CSN(R8)2 [where each R8 group may be the same or different], xe2x80x94NH2 or substituted amino group;
R2 and R3 which may be the same or different is each a hydrogen or halogen atom or a group selected from an optionally substituted aliphatic, cycloaliphatic, heteroaliphatic, heterocycloaliphatic, xe2x80x94OH, xe2x80x94OR10 [where R10 is an optionally substituted aliphatic group], xe2x80x94OR10a [where R10a is an optionally substituted cycloaliphatic, heteroaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group] xe2x80x94SH, xe2x80x94NO2, xe2x80x94CN, xe2x80x94SR8, xe2x80x94COR8, S(O)R8, xe2x80x94SO2R8, xe2x80x94SO2NH2, xe2x80x94SO2NHR8, xe2x80x94SO2N(R8)2 [where each R8 group may be the same or different] xe2x80x94CO2H, xe2x80x94CO2R8, xe2x80x94CONH2, xe2x80x94CONHR8, xe2x80x94CON(R8)2, [where each R8 group may be the same or different] xe2x80x94CSNH2, xe2x80x94CSNHR8, xe2x80x94CSN(R8)2, [where each R8 group may be the same or different] xe2x80x94NH2 or substituted amino group provided that when one or both of R2 and R3 is an xe2x80x94OR10 group then R1 is an xe2x80x94OR8 group in which R8 is an optionally substituted cycloaliphatic, heteroaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group or an aliphatic group substituted by a cyclic amino group;
R4 is a hydrogen atom or a straight or branched alkyl group;
R5 is a hydrogen atom or an optionally substituted straight or branched alkyl, alkenyl or alkynyl group;
R6 is a hydrogen or halogen atom or an amino, substituted amino, nitro, xe2x80x94CO2H, or xe2x80x94CO2R8 group or a group xe2x80x94X1xe2x80x94R6a where X1 is a direct bond or a linker atom or group and R6a is an optionally substituted straight or branched alkyl, alkenyl or alkynyl group;
R7 is an optionally substituted aliphatic, cycloaliphatic, heteroaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group; and the salts, solvates, hydrates and N-oxides thereof.
When in the compounds of formula (1) X1 is present as a linker atom or group it may be for example an xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94 atom or a xe2x80x94C(O)xe2x80x94, xe2x80x94C(S)xe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94N(R11)xe2x80x94 [where R11 is a hydrogen atom or a C1-6 alkyl, e.g. methyl or ethyl, group], xe2x80x94CON(R11)xe2x80x94, xe2x80x94OC(O)N(R11)xe2x80x94, xe2x80x94CSN(R11)xe2x80x94, xe2x80x94N(R11)COxe2x80x94, xe2x80x94N(R11)C(O)Oxe2x80x94, xe2x80x94N(R11)CSxe2x80x94, xe2x80x94SON(R11), xe2x80x94SO2N(R11), xe2x80x94N(R11)SO2xe2x80x94, xe2x80x94N(R11)CON(R11), xe2x80x94N(R11)CSN(R11), xe2x80x94N(R11)SON(R11)xe2x80x94 or xe2x80x94N(R11)SO2N(R11) group.
In the compounds of formula (1), when R1 is xe2x80x94XR8 and R8 is an optionally substituted aliphatic group, R8 may be an optionally substituted C1-10 aliphatic group for example an optionally substituted straight or branched chain C1-6 alkyl, e.g. C1-3 alkyl, C2-6 alkenyl, e.g. C2-4 alkenyl, or C2-6alkynyl, e.g. C2-4 alkynyl group. Each of said groups may be optionally interrupted by one or two heteroatoms or heteroatom-containing groups represented by X2 [where X2 is an atom or group as just described for X1], to form an optionally substituted R8 heteroaliphatic group.
Particular examples of aliphatic groups represented by R8 include optionally substituted xe2x80x94CH3, xe2x80x94CH2CH3, xe2x80x94(CH2)2CH3, xe2x80x94CH(CH3)2, xe2x80x94(CH2)3CH3, xe2x80x94CH(CH3)CH2CH3, xe2x80x94CH2CH(CH3)2, xe2x80x94C(CH3)3, xe2x80x94(CH2)4CH3, xe2x80x94(CH2)5CH3, xe2x80x94CHCH2, xe2x80x94CHCHCH3, xe2x80x94CH2CHCH2, xe2x80x94CHCHCH2CH3, xe2x80x94CH2CHCHCH3, xe2x80x94(CH2)2CHCH2, xe2x80x94CCH, xe2x80x94CCCH3, xe2x80x94CH2CCH, xe2x80x94CCCH2CH3, xe2x80x94CH2CCCH3, or xe2x80x94(CH2)2CCH groups. Where appropriate each of said groups may be optionally interrupted by one or two atoms and/or groups X2 to form an optionally substituted heteroaliphatic group. Particular examples include xe2x80x94CH2X2CH3, xe2x80x94CH2X2CH2CH3, xe2x80x94(CH2)2X2CH3 and xe2x80x94(CH2)2X2CH2CH3 groups.
The optional substituents which may be present on these aliphatic and/or heteroaliphatic groups include one, two, three or more substituents selected from halogen atoms, e.g. fluorine, chlorine, bromine or iodine atoms, or hydroxyl, C1-6 alkoxy, e.g. methoxy or ethoxy, thiol, C1-6 alkylthio e.g. methylthio or ethylthio, xe2x80x94SC(NH)NH2, xe2x80x94CH2C(NH)NH2, amino, substituted amino or cyclic amino groups.
Substituted amino groups include for example groups of formulae xe2x80x94NR9R10 [where R9 is an optionally substituted C1-6 alkyl, C2-6alkenyl or C2-6alkynyl group optionally interrupted by one or two heteroatoms or heteroatom-containing groups represented by X3 (where X3 is an atom or group as described above for X1) and R10 is a hydrogen atom or is a group as just defined for R9], xe2x80x94N(R10)COR9, xe2x80x94N(R10)CSR9, xe2x80x94N(R10)SOR9, xe2x80x94N(R10)SO2R9, xe2x80x94N(R10)CONH2, xe2x80x94N(R10)CONR9R10, xe2x80x94N(R10)C(O)OR9, xe2x80x94N(R10)C(NH)NH2, N(R10)C(NH)NR9R10, xe2x80x94N(R10)CSNH2, xe2x80x94N(R10)CSNR9R10, xe2x80x94N(R10)SONH2, xe2x80x94N(R10)SONR9R10, xe2x80x94N(R10)SONH2, xe2x80x94N(R10)SO2NH2, N(R10)SO2NR9R10, or xe2x80x94N(R10)Cyc1 [where Cyc1 is an optionally substituted C3-7 monocyclic carbocyclic group optionally containing one or more xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94 atoms or xe2x80x94N(R11)xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94C(S)xe2x80x94, xe2x80x94S(O)xe2x80x94 or xe2x80x94S(O2)xe2x80x94groups].
Cyclic amino substituents which may be present on R8 aliphatic or heteroaliphatic groups include groups of formula xe2x80x94NHet1, where xe2x80x94NHet1 is an optionally substituted C3-7cyclic amino group optionally containing one or more other heteroatoms or heteroatom containing groups selected from xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94 atoms xe2x80x94N(R11)xe2x80x94, xe2x80x94C(O), xe2x80x94C(S)xe2x80x94, xe2x80x94S(O)xe2x80x94 or xe2x80x94S(O2)xe2x80x94 groups.
Particular examples of amino, substituted amino and cyclic amino groups include xe2x80x94NH2, methylamino, ethylamino, dimethylamino, diethylamino, xe2x80x94NHCyc1 where Cyc1 is an optionally substituted cyclopentyl, cyclohexyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, morpholinyl, piperazinyl or thiomorpholinyl group, or xe2x80x94NHet1 where xe2x80x94NHet1 is an optionally substituted pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, morpholinyl, piperazinyl or thiomorpholinyl group. Optional substituents which may be present on these groups and substituted and cyclic amino groups in general include one, two or three halogen atoms, e.g. fluorine, chlorine, bromine or iodine atoms, or C1-4alkyl, e.g. methyl or ethyl, hydroxyl, or C1-4alkoxy, e.g. methoxy or ethoxy groups.
When R8 is present in compounds of formula (1) as an optionally substituted cycloaliphatic group it may be an optionally substituted C3-10cycloaliphatic group. Particular examples include optionally substituted C3-10cycloalkyl, e.g. C3-7cycloalkyl, or C3-10cycloalkenyl e.g. C3-7cycloalkenyl groups.
Heteroaliphatic or heterocycloaliphatic groups represented by R8 include the aliphatic or cycloaliphatic groups just described for R8 but with each group additionally containing one, two, three or four heteroatoms or heteroatom-containing groups represented by X2, where X2 is as described above.
Particular examples of R8 cycloaliphatic and heterocycloaliphatic groups include optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 2-cyclobuten-1-yl, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2,4-cyclopentadien-1-yl, 3,5,-cyclohexadien-1-yl, tetrahydrofuranyl, pyrroline, e.g. 2- or 3-pyrrolinyl, pyrrolidinyl, dioxolanyl, e.g. 1,3-dioxolanyl, imidazolinyl, e.g. 2-imidazolinyl, imidazolidinyl, pyrazolinyl, e.g. 2-pyrazolinyl, pyrazolidinyl, pyranyl, e.g. 2- or 4-pyranyl, piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl, piperazinyl, 1,3,5-trithianyl, oxazinyl, e.g. 2H-1,3-, 6H-1,3-, 6H-1,2-, 2H-1,2- or 4H-1,4- oxazinyl, 1,2,5-oxathiazinyl, isoxazinyl, oxathiazinyl, e.g. 1,2,5 or 1,2,6-oxathiazinyl, or 1,3,5-oxadiazinyl groups.
Optional substituents which may be present on R8 cycloaliphatic and heterocycloaliphatic groups include those optional substituents described above for R8 when it is an aliphatic group. The heterocycloaliphatic groups may be attached to the remainder of the molecule of formula (1) through any appropriate ring carbon or heteroatom.
When R8 is present as an aromatic group in compounds of formula (1) it may be for example an optionally substituted monocyclic or bicyclic fused ring C6-12 aromatic group, such as an optionally substituted phenyl, 1- or 2-naphthyl, 1- or 2-tetrahydronaphthyl, indanyl or indenyl group.
Heteroaromatic groups represented by R8 include optionally substituted C1-9 heteroaromatic groups containing for example one, two, three or four heteroatoms selected from oxygen, sulphur or nitrogen atoms. In general, the heteroaromatic groups may be for example monocyclic or bicyclic fused ring heteroaromatic groups. Monocyclic heteroaromatic groups include for example live- or six-membered heteroaromatic groups containing one, two, three or four heteroatoms selected from oxygen, sulphur or nitrogen atoms. Bicyclic heteroaromatic groups include for example nine- to thirteen-membered fused-ring heteroaromatic groups containing one, two or more heteroatoms selected from oxygen, sulphur or nitrogen atoms.
Examples of heteroaromatic groups represented by R8 include optionally substituted pyrrolyl, furyl, thienyl, imidazolyl, N-methylimidazolyl, N-ethyl-imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazole, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, benzofuryl, [2,3-dihydroabenzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, isobenzothienyl, indolyl, isoindolyl, benzimidazolyl imidazo[1,2-a]pyridyl, benzothiazolyl, benzoxazolyl, benzopyranyl, [3,4-dihydro]benzopyranyl, quinazolinyl, naphthyridinyl, pyrido[3,4-b]pyridyl, pyrido[3,2-b]pyridyl, pyrido[4,3-b]pyridyl, quinolinyl, isoquinolinyl, tetrazolyl, 5,6,7,8-tetrahydroquinolinyl, 5,6,7,8-tetrahydroisoquinolinyl, and imidyl, e.g. succinimidyl, phthalimidyl, or naphthalimidyl such as 1,8-naphthalimidyl.
Optional substituents which may be present on any of the above aromatic or heteroaromatic groups in compounds of formula (1) include one, two, three or more substituents, each represented by the group R12. The substituent R12 may be selected from an atom or group R13 or xe2x80x94Alk(R13)m, where R13 is a halogen atom, or an amino (xe2x80x94NH2), xe2x80x94NHR14 [where R14 is an xe2x80x94Alk(R13)m, heterocycloalkyl, xe2x80x94Alk-heterocycloalkyl, aryl or heteroaryl group], xe2x80x94N(R14)2 [where each R14 group is the same or different], nitro, cyano, hydroxyl (xe2x80x94OH), xe2x80x94OR14, formyl, carboxyl (xe2x80x94CO2H), esterified carboxyl, thiol (xe2x80x94SH), xe2x80x94SR14, xe2x80x94COR14, xe2x80x94CSR14, xe2x80x94SO3H, xe2x80x94SO2R14, xe2x80x94SO2NH2, xe2x80x94SO2NHR14, SO2N[R14]2, xe2x80x94CONH2, xe2x80x94CSNH2, xe2x80x94CONHR14, xe2x80x94CSNHR14, xe2x80x94CON[R14]2, xe2x80x94CSN[R14]2, xe2x80x94N(R11)SO2H [where R11 is as defined above], xe2x80x94N(R11)SO2R14, xe2x80x94N[SO2R14]2, xe2x80x94N(R11)SO2 NH2, xe2x80x94N(R11)SO2NHR14, xe2x80x94N(R11)SO2N[R14]2, xe2x80x94N(R11)COR14, xe2x80x94N(R11)CONH2, xe2x80x94N(R11)CONHR14, xe2x80x94N(R11)CON[R14]2, xe2x80x94N(R11)CSR14, xe2x80x94N(R11)CSNH2, xe2x80x94N(R1 )CSNHR14, xe2x80x94N(R11)CSN[R14]2, xe2x80x94N(R11)C(O)OR14, or an optionally substituted cycloalkyl, aryl or heteroaryl group; Alk is a straight or branched C1-6 alkylene, C2-6 alkenylene or C2-6 alkynylene chain, optionally interrupted by one, two or three xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94 atoms or Sxe2x80x94(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94 or xe2x80x94N(R11)xe2x80x94 groups; and m is zero or an integer 1, 2 or 3.
When in the group xe2x80x94Alk(R13)m m is an integer 1, 2 or 3, it is to be understood that the substituent or substituents R13 may be present on any suitable carbon atom in xe2x80x94Alk. Where more than one R13 substituent is present these may be the same or different and may be present on the same or different atom in xe2x80x94Alk or in R7 as appropriate. Thus for example, R7 may represent a xe2x80x94CH(R13)2 group, such as a xe2x80x94CH(OH)Ar group where Ar is an aryl or heteroaryl group as defined below. Clearly, when m is zero and no substituent R13 is present the alkylene, alkenylene or alkynylene chain represented by Alk becomes an alkyl, alkenyl or alkynyl group.
When R13 is a halogen atom it may be for example a fluorine, chlorine, bromine, or iodine atom.
Esterified carboxyl groups represented by the group R13 include groups of formula xe2x80x94CO2Alk1 wherein Alk1 is a straight or branched, optionally substituted C1-8 alkyl group such as a methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl or t-butyl group; a C6-12arylC1-8alkyl group such as an optionally substituted benzyl, phenylethyl, phenylpropyl, 1-naphthylmethyl or 2-naphthylmethyl group; a C6-12aryl group such as an optionally substituted phenyl, 1-naphthyl or 2-naphthyl group; a C6-12aryloxyC1-8alkyl group such as an optionally substituted phenyloxymethyl, phenyloxyethyl, 1-naphthyloxymethyl, or 2-naphthyloxymethyl group; an optionally substituted C1-8alkanoyloxyC1-8alkyl group, such as a pivaloyloxymethyl, propionyloxyethyl or propionyloxypropyl group; or a C6-12aroyloxyC1-8alkyl group such as an optionally substituted benzoyloxyethyl or benzoyl-oxypropyl group. Optional substituents present on the Alk1 group include R13 substituents described above.
When Alk is present in or as a substituent R12 it may be for example a methylene, ethylene, n-propylene, i-propylene, n-butylene, i-butylene, s-butylene, t-butylene, ethenylene, 2-propenylene, 2-butenylene, 3-butenylene, ethynylene, 2-propynylene, 2-butynylene or 3-butynylene chain, optionally interrupted by one, two, or three xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, atoms or xe2x80x94S(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94 or xe2x80x94N(R11) groups.
Optionally substituted cycloalkyl groups represented by the group R13 include optionally substituted C5-7 cycloalkyl groups such as optionally substituted cyclopentyl or cyclohexyl groups.
Heterocycloalkyl groups represented by the group R12 or R14 include optionally substituted heteroC3-6cycloalkyl groups containing one or two oxygen, sulphur or nitrogen atoms. Particular examples of such groups include optionally substituted azetidinyl pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, morpholinyl or thiomorpholinyl groups. The heterocycloalkyl group may be attached to the remainder of the molecule through any of its ring carbon atoms, or where present, ring nitrogen atom. Where the group R12 is an xe2x80x94Alk-heterocycloalkyl group, Alk may be as defined above and the heterocycloalkyl portion may be as just defined, attached to Alk through any of its ring carbon atoms, or where present, ring nitrogen atom.
Optional substituents which may be present on R12, R13 or R14 cycloalkyl or heterocycloalkyl groups include one or two C1-6 alkyl, e.g. methyl or ethyl, hydroxyl (xe2x80x94OH) hydroxyC1-6alkyl, e.g. hydroxymethyl or hydroxyethyl, or C1-6 alkoxy, e.g. methoxy or ethoxy groups. The substituent(s) may be present on any available ring carbon or nitrogen atom as appropriate.
Aryl and heteroaryl groups represented by the groups R13 or R14 include for example optionally substituted monocyclic or bicyclic C6-12 aromatic groups, or C1-9 heteroaromatic groups such as those described above in relation to the group R8.
Particularly useful atoms or groups represented by R12 include fluorine, chlorine, bromine or iodine atoms, or C1-6alkyl, C1-6 alkylamino, C1-6hydroxyalkyl, C1-6alkylthiol, C1-6alkoxy, hydroxyC1-6alkoxy, aminoC1-6alkoxy, C1-6alkylaminoC1-6alkoxy, C1-6dialkylaminoC1-6akoxy, optionally substituted C5-7cyclo-alkoxy, optionally substituted C5-7cycloalkyl, optionally substituted C5-7cycloalkylamino, haloC1-6alkyl, haloC1-6alkoxy, C1-6alkylamino, amino (xe2x80x94NH2), aminoC1-6alkyl, C1-6dialkylamino, hydroxyC1-6 alkylamino, aminoC1-6alkylamino, C1-6alkylaminoC1-6alkylamino, C1-6dialkylaminoC1-6alkylamino, C1-6alkylaminoC1-6 dialkylamino, C1-6dialkylaminoC1-6dialkylamino, nitro, cyano, hydroxyl (xe2x80x94OH), formyl [HC(O)xe2x80x94], carboxyl (xe2x80x94CO2H), xe2x80x94CH2CO2H, xe2x80x94OCH2CO2H, xe2x80x94CO2Alk1 [where Alk1 is as defined above], xe2x80x94CH2CO2Alk1, C1-6alkoxycarbonylC1-6alkoxy, C1-6 alkanoyl, optionally substituted phenyl C1-6alkanoyl, thiol (xe2x80x94SH), thioC1-6alkyl, xe2x80x94SC(NH)NH2, sulphonyl (xe2x80x94SO3H), C1-6alkylsulphonyl, optionally substituted phenylsulphonyl, aminosulphonyl (xe2x80x94SO2NH2), C1-6alkylaminosulphonyl, C1-6dialkylaminosulphonyl, optionally substituted phenylamino-sulphonyl, carboxamido (xe2x80x94CONH2), C1-6alkyl-aminocarbonyl, C1-6dialkylaminocarbonyl, optionally substituted phenyl-aminocarbonyl, aminocarbonylmethyl, C1-6alkylaminocarbonylmethyl, optionally substituted benzylaminocarbonylmethyl, xe2x80x94NHC(S)NH2, sulphonyl-amino (xe2x80x94NHSO2H), C1-6alkylsulphonylamino, C1-6dialkylsulphonylamino, optionally substituted phenylsulphonylamino, aminosulphonylamino (xe2x80x94NHSO2NH2), C1-6alkylaminosulphonylamino, C1-6dialkylaminosulphonylamino, optionally substituted phenylaminosulphonylamino, aminocarbonyl-amino, C1-6alkylaminocarbonylamino C1-6dialkylaminocarbonylamino, phenylaminocarbonylamino, C1-6alkanoylamino, aminoC1-6 alkanoylamino, optionally substituted pyridylcarboxyamino, C1-6alkanoylaminoC1-6alkyl, C1-6alkoxycarbonylamino, optionally substituted heteroC3-6cycloalkyl, piperidinyl, piperazinyl, 4-methylpiperazinyl, homopipeprazinyl, or morpholinyl, optionally substituted heteroC3-6cycloalkylC1-6alkyl, piperidinylC1-6alkyl, piperazinylC1-6alkyl or morpholinylC1-6alkyl, optionally substituted heteroC3-6alkylC1-6alkylamino, optionally substituted heteroC3-6cycloalkylamino, tetrazolyl, optionally substituted phenylamino, optionally substituted benzylamino, optionally substituted benzyloxy, or optionally substituted pyridiylmethylamino group.
Where desired, two R12 substituents may be linked together to form a cyclic group such as a cyclic ether, e.g. a C1-6alkylenedioxy group such as a methylenedioxy or ethylenedioxy group.
Especially useful R12 substituents include for example fluorine, chlorine, bromine or iodine atoms, or a methylamino, ethylamino, hydroxymethyl, hydroxyethyl, methylthiol, ethylthiol, methoxy, ethoxy, n-propoxy, 2-hydroxyethoxy, 3-hydroxypropoxy, 4-hydroxybutoxy, 2-aminoethoxy, 3-aminopropoxy, 2-(methylamino)ethoxy, 2-(dimethylamino)ethoxy, 3-(dimethylamino)propoxy, cyclopentyloxy, cyclohexyl, cyclohexylamino, 2-hydroxycyclohexylamino, trifluoromethyl, trifluoromethoxy, methylamino, ethylamino, amino (xe2x80x94NH)2, aminomethyl, aminoethyl, dimethylamino, diethylamino, ethyl(methyl)amino, propyl(methyl)amino, 2-hydroxyethylamino, 3-hydroxypropylamino, 4-hydroxybutylamino, 2-aminoethylamino, 3-aminopropylamino, 4-aminobutylamino, 2-(methylamino)ethylamino, 2-(ethylamino)ethylamino, 2-(i-propylamino)ethylamino, 3-(i-propylamino)-propylamino, 2-(dimethylamino)ethylamino, 3-(dimethylamino)propylamino, 2-(diethylamino)ethylamino, 3-(diethylamino)propylamino, 2-(methylamino)-ethyl(methyl)amino, 3-(methylamino)propyl(methyl)amino, 2-(dimethyl-amino)ethyl(methyl)amino, 2-(dimethylamino)ethyl(ethyl)amino, nitro, cyano, hydroxyl (xe2x80x94OH), formyl [HC(O)xe2x80x94], carboxyl (xe2x80x94CO2H), xe2x80x94CH2CO2H, xe2x80x94OCH2CO2H, xe2x80x94CO2CH3, xe2x80x94CO2CH2CH3, xe2x80x94CH2CO2CH3, xe2x80x94CH2CO2CH2CH3, xe2x80x94CH2CO2CH2phenyl, t-butoxycarbonylmethoxy, acetyl, phenacetyl, thio (xe2x80x94SH), thiomethyl, thioethyl, xe2x80x94SC(NH)NH2, sulphonyl (xe2x80x94SO2 H), methylsulphonyl, methylaminosulphonyl, ethylaminosulphonyl, dimethylaminosulphonyl, diethylaminosulphonyl, carboxamido (xe2x80x94CONH2), methylaminocarbonyl, ethylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, methylaminocarbonylmethyl, xe2x80x94NHC(S)NH2, sulphonylamino (xe2x80x94NHSO2H), methylsulphonylamino ethylsulphonylamino, dimethylsulphonylamino, diethylsulphonylamino, sulphonylamino (xe2x80x94NHSO2NH2), methylaminosulphonylamino, ethylaminosulphonylamino, dimethylaminosulphonylamino, diethylaminosulphonylamino, methylaminocarbonylamino, ethylaminocarbonylamino, dimethylaminocarbonylamino diethylaminocarbonylamino, acetylamino, aminomethylcarbonylamino, acetylaminomethyl, methoxycarbonylamino, ethoxycarbonylamino, t-butoxycarbonylamino, pyrrolidinyl, piperidinyl, piperazinyl, 4-methylpiperazinyl, homopipeprazinyl, morpholinyl, pyrrolidinylC1-6alkyl, piperidinylC1-6alkyl, piperazinylC1-6alkyl, morpholinylC1-6alkyl, 2-pyrrolidinylethylamino, 2-(1-methylpyrrolidinyl)ethylamino, 1-ethylpyrrolidinylmethylamino, piperidinylamino, 1-benzylpiperidinylamino, 4-(methoxy)phenylamino, 4-(3-hydroxypropyl)phenylamino, benzylamino, benzyloxy, pyridiylmethylamino group.
It will be appreciated that where two or more R12 substituents are present, these need not necessarily be the same atoms and/or groups.
In general, when R8 is a heteroaliphatic, heterocycloaliphatic or heteroaromatic group it is attached to the remainder of the molecule of formula (1) through any available heteroatom or group or, preferably, carbon atom.
The groups R2, R3, R7 and additionally R10 and/or R10a [where present] in compounds of formula (1) may each individually be an optionally substituted aliphatic, cycloaliphatic, heteroaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group. In each case, the aliphatic, cycloalphatic, heteroaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group may be as particularly described above for R8 when it represents one of these groups.
Halogen atoms represented by the groups R2, R3 and/or R6 in compounds of formula (1) include for example fluorine, chlorine, bromine or iodine atoms.
Substituted amino groups represented by the groups R1, R2, R3 and/or R6 in compounds of formula (1) include groups such as xe2x80x94NHR15 [where R15 is an optionally substituted straight or branched C1-6alkyl, C2-6alkenyl or C2-6alkynyl group], xe2x80x94NR15R16 [where R15 and R16 are the same or different and R16 is an optionally substituted alkyl, alkenyl or alkynyl group as just described for R15], xe2x80x94N(R17)COR15, [where R17 is a hydrogen atom or a group R15 as just described], xe2x80x94N(R17)SO2R18 [where R18 is as described for R17] xe2x80x94N[SO2R18]2, xe2x80x94N(R17)SO2NR17R18, xe2x80x94N(R17)CONR17R18, or xe2x80x94N(R17)CSNR17R18. Particular examples of R15, R16, R17 and R18 alkyl, alkenyl or alkynyl groups include optionally substituted methyl, ethyl, n-propyl, i-propyl, allyl or ethynyl groups. Optional substituents include those described above in relation to the group R8 when R8 is an optionally substituted aliphatic group.
Particular examples of substituted amino groups represented by R2, R3 and/or R6 include xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94NHCH2CH3, xe2x80x94N(CH2CH3)2, xe2x80x94NHCOCH3, xe2x80x94NHSO2 H, xe2x80x94NHSO2CH3, xe2x80x94NHSO2 NH2, xe2x80x94NHSO2 NHCH3, xe2x80x94NHSO2N(CH3)2, xe2x80x94NHCONH2, xe2x80x94NHCONHCH3 or xe2x80x94NHCONHCH2CH3 groups.
Optionally substituted straight or branched alkyl, alkenyl or alkynyl groups represented by R5 and/or R6a [when present] include optionally substituted C1-6alkyl, C2-6alkenyl or C2-6alkynyl as described above for R8 aliphatic groups.
Straight or branched alkyl groups represented by the group R4 in compounds of the invention include straight or branched C1-6alkyl groups such as methyl or ethyl groups.
The presence of certain substituents in the compounds of formula (1) may enable salts of the compounds to be formed. Suitable salts include pharmaceutically acceptable salts, for example acid addition salts derived from inorganic or organic acids, and salts derived from inorganic and organic bases.
Acid addition salts include hydrochlorides, hydrobromides, hydroiodides, alkylsulphonates, e.g. methanesulphonates, ethanesulphonates, or isethionates, arylsulphonates, e.g. p-toluenesulphonates, besylates or napsylates, phosphates, sulphates, hydrogen sulphates, acetates, trifluoroacetates, propionates, citrates, maleates, fumarates, malonates, succinates, lactates, oxalates, tartrates and benzoates.
Salts derived from inorganic or organic bases include alkali metal salts such as sodium or potassium salts, alkaline earth metal salts such as magnesium or calcium salts, and organic amine salts such as morpholine, piperidine, dimethylamine or diethylamine salts.
Particularly useful salts of compounds according to the invention include pharmaceutically acceptable salts, especially acid addition pharmaceutically acceptable salts.
It will be appreciated that depending on the nature of the substituents R1-R3 and R5-R7 the compounds of formula (1) may exist as geometrical isomers and/or may have one or more chiral centres so that enantiomers or diasteromers may exist. It is to be understood that the invention extends to all such isomers of the compounds of formula (1), and to mixtures thereof, including racemates.
In one class of compounds of formula (1) the groups R1, R2, R3, R4, R5, R7 and X are as defined for formula (1), and R6 is a hydrogen or halogen atom or a group xe2x80x94X1xe2x80x94R6a.
In a further preferred class of compounds of formula (1) R4 is especially a hydrogen atom.
The groups R5 and R6 in compounds of formula (1) are each preferably a hydrogen atom.
R7 in compounds of formula (1) is preferably an optionally substituted aromatic or heteroaromatic group.
A further class of compounds according to the invention has the formula 1 (a): 
wherein each of R1, R2, R3, R4, R5, R6 and R7 is as defined for formula (1); and the salts, solvates, hydrates and N-oxides thereof.
In these compounds, R4 and R5 is each preferably a hydrogen atom. R6 is preferably a group xe2x80x94X1R6a where X1 is as defined for formula (1) and R6a is an optionally substituted straight or branched chain alkyl group, or R6 is especially a hydrogen atom. R7 in compounds of formula (1a) is preferably an optionally substituted aromatic or heteroaromatic group.
The aromatic or heteroaromatic R7 group in compounds of formulae (1) or 1 (a) in general may be as defined previously for compounds of formula (1). In one preference, however, R7 is an optionally substituted phenyl, 1- or 2-naphthyl or heteroaromatic group containing one or two oxygen, sulphur and/or nitrogen atoms. Thus in particular R7 may be an optionally substituted phenyl, 1- or 2-naphthyl, pyrrolyl, furyl, thienyl, indolyl, pyrazolyl, thiazolyl, [2,3-dihydro]benzofuryl, benzothiazolyl, 2-pyridyl, 3-pyridyl or 4-pyridyl group. Particularly useful groups include optionally substituted phenyl, particularly 3-substituted phenyl groups, 2-pyridyl, 3-pyridyl or 4-pyridyl groups. The aromatic or heteroaromatic group may in particular be attached to the remainder of the compound of formula (1) through any available ring carbon atom.
In general, the optional substituents which may be present on aromatic or heteroaromatic R7 groups in compounds of formulae (1) or (1a) include one, two, or three R12 substituents as generally and particularly described above and hereinafter in the Examples. Particularly useful R12 substituents include xe2x80x94NHR14, xe2x80x94AlkNH2, xe2x80x94AlkNHR14, xe2x80x94OR14, xe2x80x94AlkCO2H or xe2x80x94AlkCO2Alk1 groups where R14, Alk and Alk1 are as generally and particularly defined above. Useful members of these substituents include those wherein R14 is an xe2x80x94Alk, xe2x80x94AlkNH2 or xe2x80x94Alk-heterocycloalkyl group. In these, and the other preferred substituents just mentioned, Alk and Alk1 when present is each preferably a C1-6alkyl group.
In the compounds of formula (1) and (1a) R1 is preferably an xe2x80x94R8 or in particular an xe2x80x94OR8 group. The group R1 is preferably attached at the 3- or 4- position of the phenyl ring. When R1 is at the 3- position any R2 and/or R3 substituent is preferably at the 4- and/or 5- positions. When R1 is at the 4- position any R2 and/or R3 substituent is preferably attached at the 3- and/or 5- positions.
Particularly useful xe2x80x94R8 groups include heterocycloaliphatic groups of the type generally described above, especially optionally substituted C3-7 cycloalkyl groups containing one or two heteroatoms such as pyrrolidinyl or morpholinyl groups. Particularly useful xe2x80x94OR8 groups include optionally substituted alkoxy groups such as optionally substituted ethoxy groups. Particularly useful substituents include amino or substituted amino groups or, especially, xe2x80x94NHet1 groups where xe2x80x94NHet1 is as defined above.
In these last compounds, and in general, the groups R2 and R3 is each preferably a methyl or methoxy group or a hydrogen atom.
Particularly useful compounds according to the invention are:
4-(3-methoxyphenylsulphanyl)-N{[3,5-dimethyl4(2-(pyrrolidin-1-yl)-ethoxy]phenyl}-2-pyrimidineamine;
4-(3-Carboxyphenylsuphanyl)-N-{[3,5-dimethyl-4-(2-pyrrolidin-1-yl) -ethoxy]phenyl}-2-pyrimidineamine;
N-[4,5-Dimethoxy-3-(2-pyrrolidin-1-ylethoxy)]-4-(3-methoxyphenylsulphanyl)-2-pyrimidineamine;
4-(3-Methoxyphenylsulphanyl)-N-{4-methoxy-[3-(2-pyrrolidin-1-yl)-ethoxy]phenyl}2-pyrimidineamine;
N-{3,5-Dimethoxy-4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}-4-(3-methoxyphenylsulphanyl)-2-pyrimidineamine;
N-{[4,5-Dimethoxy-3-(2-pyrrolin-1-yl)ethoxy]phenyl}4-(4-fluorophenylsulphanyl) pyrimidine-2-amine;
4-(3-Bromophenylsulphanyl)-N-[4,5-dimethoxy-3-(2-pyrrolidin-1-yl-ethoxy)phenyl]-2-pyrimidineamine;
N-{3,5-Dichloro-4-[(2-pyrrolidin-1-yl)ethoxy]phenyl}-4-(3,5-dimethylphenylsulphanyl)-2-pyrimidineamine;
and the salts, solvates and hydrates thereof.
Compounds according to the invention are potent and selective inhibitors of protein kinases, especially those of the src family, as demonstrated by their inhibition of enzymes such as p56lck and p59fyn. The ability of the compounds to act in this way may be simply determined by employing tests such as those described in the Examples hereinafter.
The compounds according to the invention are thus of particular use in the prophylaxis and treatment of diseases in which inappropriate protein tyrosine kinase action plays a role, for example in autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, and systemic lupus erythematosus, in transplant rejection, in graft v host disease, in hyperproliferative disorders such as tumours, psoriasis, in pannus formation in rheumatoid arthritis, restenosis following angioplasty and atherosclerosis, in osteoporosis and in diseases in which cells receive pro-inflammatory signals such as asthma, inflammatory bowel disease and pancreatitis.
For the prophylaxis or treatment of disease the compounds according to the invention may be administered as pharmaceutical compositions, and according to a further aspect of the invention we provide a pharmaceutical composition which comprises a compound of formula (1) together with one or more pharmaceutically acceptable carriers, excipients or diluents.
Pharmaceutical compositions according to the invention may take a form suitable for oral, buccal, parenteral, nasal, topical or rectal administration, or a form suitable for administration by inhalation or insufflation.
For oral administration, the pharmaceutical compositions may take the form of, for example, tablets, lozenges or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium glycollate); or wetting agents (e.g. sodium lauryl sulphate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents, emulsifying agents, non-aqueous vehicles and preservatives. The preparations may also contain buffer salts, flavouring, colouring and sweetening agents as appropriate.
Preparations for oral administration may be suitably formulated to give controlled release of the active compound.
For buccal administration the compositions may take the form of tablets or lozenges formulated in conventional manner.
The compounds for formula (1) may be formulated for parenteral administration by injection e.g. by bolus injection or infusion. Formulations for injection may be presented in unit dosage form, e.g. in glass ampoule or multi dose containers, e.g. glass vials. The compositions for injection may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising, preserving and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
In addition to the formulations described above, the compounds of formula (1) may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation or by intramuscular injection.
For nasal administration or administration by inhalation, the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation for pressurised packs or a nebuliser, with the use of suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or mixture of gases.
The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack or dispensing device may be accompanied by instructions for administration.
The quantity of a compound of the invention required for the prophylaxis or treatment of a particular condition will vary depending on the compound chosen, and the condition of the patient to be treated. In general, however, daily dosages may range from around 100 ng/kg to 100 mg/kg e.g. around 0.01 mg/kg to 40 mg/kg body weight for oral or buccal administration, from around 10 ng/kg to 50 mg/kg body weight for parenteral administration and around 0.05 mg to around 1000 mg e.g. around 0.5 mg to around 1000 mg for nasal administration or administration by inhalation or insufflation.
The compounds of the invention may be prepared by a number of processes as generally described below and more specifically in the Examples hereinafter. In the following process description, the symbols R1-R7 when used in the formulae depicted are to be understood to represent those groups described above in relation to formula (1) unless otherwise indicated. In the reactions described below, it may be necessary to protect reactive functional groups, for example hydroxy, amino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions. Conventional protecting groups may be used in accordance with standard practice [see, for example, Green, T. W. in xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, John Wiley and Sons, 1991]. In some instances, deprotection may be the final step in the synthesis of a compound of formula (1) and the processes according to the invention described hereinafter are to be understood to extend to such removal of protecting groups.
Thus according to one aspect of the invention, a compound of formula (1) wherein R4 is a hydrogen atom may be prepared by displacement of a leaving atom or group in a pyrimidine of formula (2): 
[where L is a leaving atom or group] with an aniline of formula (3): 
Particular leaving atoms or groups represented by L include for example halogen atoms, e.g. bromine, iodine or chlorine atoms, and sulphonyloxy groups, e.g. alkylsulphonyloxy groups, such as trifluoromethylsulphonyloxy, and arylsulphonyloxy groups, such as p-toluenesulphonyloxy.
The reaction may be performed at an elevated temperature, for example the reflux temperature, where necessary in the presence of a solvent, for example a ketone such as acetone, an alcohol such as ethanol or 2-ethoxyethanol or an aromatic hydrocarbon such as toluene, optionally in the presence of a base, for example an organic amine such as triethylamide or pyridine, or an acid, for example an inorganic acid such as hydrochloric acid.
Intermediate pyrimidines of formula (2) are either known readily available compounds or may be prepared by displacement of a leaving group from a pyrimidine of formula (4): 
[where L1 is a leaving atom or group as described above for the group L] using a thiol R7SH. The reaction may be performed in the presence of a base such as sodium hydride in a solvent such as an amide, e.g. dimethylformamide at a low temperature of around 0xc2x0 C.
The pyrimidines of formula (4) and the nucleophilic reagents R7SH are either known compounds or may be prepared using methods analogous to those used for the preparation of the known compounds.
The anilines of formula (3) are either known compounds or may be obtained by conventional procedures, for example by hydrogenation of the corresponding nitro derivatives using for example hydrogen in the presence of a metal catalyst in a suitable solvent, for example as more particularly described in the interconversion reactions discussed below, or by use of the corresponding nitro derivative and a reducing agent such as sodium hydrosulphite in a solvent such as ethanol at an elevated temperature such as the reflux temperature. The nitrobenzenes for this particular reaction are either known compounds or may be prepared using similar methods to those used for the preparation of the known compounds, for example by treatment of the corresponding benzene with nitric acid in the presence of an acid such as acetic acid at around ambient to the reflux temperature.
Compounds of formula (1) may also be prepared by interconversion of other compounds of formula (1) and it is to be understood that the invention extends to such interconversion processes. Thus, for example, standard substitution approaches employing for example alkylation, arylation, acylation, thioacylation, sulphonylation, formulation or coupling reactions may be used to add new substituents to and/or extend existing substituents in compounds of formula (1). Alternatively existing substituents in compounds of formula (1) may be modified by for example oxidation, reduction or cleavage reactions to yield other compounds of formula (1).
The following describes in general terms a number of approaches which can be employed to modify existing R1, R2, R3, R4, R5, R6 and/or R7 groups in compounds of formula (1). It will be appreciated that each of these reactions may only be possible where an appropriate functional group exists in a compound of formula (1). Equally, any of the following reactions may be used to generate appropriately substituted intermediates of formulae (2), (3) and (4) for use in the preparation of compounds of formula (1).
Thus, for example alkylation or arylation of a compound of formula (1) may be achieved by reaction of the compound with a reagent R8L (where R8 is as defined above except for a hydrogen atom) or (R13)mAlkL where L is as previously defined.
The alkylation or arylation reaction may be carried out in the presence of a base, e.g. an inorganic base such as a carbonate, e.g. caesium or potassium carbonate, an alkoxide, e.g. potassium t-butoxide, or a hydride, e.g. sodium hydride, in a dipolar aprotic solvent such as an amide, e.g. a substituted amide such as dimethylformamide or an ether, e.g. a cyclic ether such as tetrahydrofuran, at around 0xc2x0 C. to around 40xc2x0 C.
In a variation of this process the leaving group L may be alternatively part of the compound of formula (1) and the reaction performed with an appropriate nucleophilic reagent such as an amine in a solvent such as an alcohol, e.g. ethanol, or an amide such as dimethylformamide at an elevated temperature, e.g. the reflux temperature.
In another general example of an interconversion process, a compound of formula (1) may be acylated or thioacylated. The reaction may be performed for example with an acyl halide or anhydride in the presence of a base, such as a tertiary amine e.g. triethylamine in a solvent such as a halogenated hydrocarbon, e.g. dichloromethane or carbon tetrachloride, or an alcohol, e.g. methanol at for example ambient temperature, or by reaction with a thioester in an inert solvent such as tetrahydrofuran at a low temperature such as around 0xc2x0 C. The reaction is particularly suitable for use with compounds of formula (1) containing primary or secondary amino groups.
In a further general example of an interconversion process, a compound of formula (1) may be formulated, for example by reaction of the compound with a mixed anhydride HCOOCOCH3 or with a mixture of formic acid and acetic anhydride.
Compounds of formula (1) may be prepared in another general interconversion reaction by sulphonylation, for example by reaction of the compound with a reagent (R13)mAlkS(O)2L, or R8S(O)2L in the presence of a base, for example an inorganic base such as sodium hydride in a solvent such as an amide, e.g. a substituted amide such as dimethylformamide at for example ambient temperature. The reaction may in particular be performed with compounds of formula (1) possessing a primary or secondary amino group. In further examples of interconversion reactions according to the invention compounds of formula (1) may be prepared from other compounds of formula (1) by modification of existing functional groups in the latter.
Thus in one example, ester groups xe2x80x94CO2Alk1 in compounds of formula (1) may be converted to the corresponding acid [xe2x80x94CO2H] by acid- or base-catalysed hydrolysis or by catalytic hydrogenation depending on the nature of the group Alk1. Acid- or base-catalysed hydrolysis may be achieved for example by treatment with an organic or inorganic acid, e.g. trifluoroacetic acid in an aqueous solvent or a mineral acid such as hydrochloric acid in a solvent such as dioxan or an alkali metal hydroxide, e.g. lithium hydroxide in an aqueous alcohol, e.g. aqueous methanol. Catalytic hydrogenation may be carried out using for example hydrogen in the presence of a metal catalyst, for example palladium on a support such as carbon in a solvent such as an ether, e.g. tetrahydrofuran or an alcohol, e.g. methanol. Similarly, base-catalysed hydrolysis with for example an alkali metal hydroxide such as sodium hydroxide in a solvent such as an alcohol e.g. ethanol may be used to convert a  greater than NSO2Alk(R13)m or  greater than NSO2R8 group to a  greater than Nxe2x80x94H group.
In a second example, xe2x80x94OAlk2 [where Alk2 represents an alkyl group such as a methyl group] groups in compounds of formula (1) may be cleaved to the corresponding alcohol [xe2x80x94OH] by reaction with boron tribromide in a solvent such as a halogenated hydrocarbon, e.g. dichloromethane at a low temperature, e.g. around xe2x88x9278xc2x0 C.
Alcohol [xe2x80x94OH] groups may also be obtained by hydrogenation of the corresponding xe2x80x94OCH2R8 group in which R8 is an aromatic group using for example hydrogen in the presence of a metal catalyst, for example palladium on a support such as carbon in a solvent such as ethanol in the presence of ammonium formate. In another example, xe2x80x94OH groups may be generated from the corresponding ester [xe2x80x94CO2Alk] by reduction using for example a complex metal hydride such as lithium aluminium hydride.
In a further example, alcohol xe2x80x94OH groups in compounds of formula (1) may be converted to a corresponding xe2x80x94OAlk(R13)m or xe2x80x94OR8 group where R8 is as described for formula (1) other than a hydrogen atom by coupling with a reagent (R13)mAlkOH or R8OH in a solvent such as tetrahydrofuran in the presence of a phosphine, e.g. triphenylphosphine and an activator such as diethyl-, diisopropyl-, or dimethylazodicarboxylate.
In another example of an interconversion reaction, amines of formula (1) may be alkylated using a reductive alkylation process employing an aldehyde and a borohydride, for example sodium triacetoxyborohydride, in a solvent such as dichloromethane, in the presence of an acid such as acetic acid at around ambient temperature.
In a further example, amide groups in compounds of formula (1) may be obtained by coupling an acid [xe2x80x94CO2H] or an active derivative thereof, e.g. an acid anhydride, ester, imide or halide, with an amine in which either the acid or amine forms part of the starting material of formula (1). The coupling reaction may be performed using standard conditions for reactions of this type. Thus for example the reaction may be carried out in a solvent, for example an inert organic solvent such as an amide, e.g. a substituted amide such as dimethylformamide, at a low temperature, e.g. xe2x88x9230xc2x0 C. to ambient temperature, optionally in the presence of a base, e.g. an organic base such as a cyclic amine, e.g. N-methylmorpholine, and where necessary in the presence of a condensing agent, for example a diimide such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide advantageously in the presence of a catalyst such as a N-hydroxy compound, e.g. a N-hydroxytriazole such as hydroxyazabenzotriazole.
Urea groups in compounds of formula (1) may be prepared by reaction of a corresponding amine [xe2x80x94NH2] with an isocyanate, e.g. ethyl isocyanate, in a solvent, e.g. dichloromethane, at ambient temperature
Aminosulphonylamino [xe2x80x94NHSO2NH2] groups in compounds of formula (1) may be obtained, in another example, by reaction of a corresponding amine [xe2x80x94NH2] with sulphamide in the presence of an organic base such as pyridine at an elevated temperature, e.g. the reflux temperature.
In a further example, amine [xe2x80x94NH2] groups in compounds of formula (1) may be obtained by hydrolysis from a corresponding imide by reaction with hydrazine in a solvent such as an alcohol, e.g. ethanol at ambient temperature.
In another example, a nitro [xe2x80x94NO2] group may be reduced to an amine [xe2x80x94NH2], for example by catalytic hydrogenation as just described, or by chemical reduction using for example a metal, e.g. tin or iron, optionally in the presence of an acid such as hydrochloric acid and a solvent such as an alcohol, e.g. methanol or ethanol.
In a further example of an interconversion process, a tetrazole substituent may be obtained from the corresponding nitrile by treatment of the latter with an azide, e.g. sodium azide, in a solvent such as a substituted amine, e.g. dimethylformamide at an elevated temperature.
N-oxides of compounds of formula (1) may be prepared for example by oxidation of the corresponding nitrogen base using an oxidising agent such as hydrogen peroxide in the presence of an acid such as acetic acid, at an elevated temperature, for example around 70xc2x0 C. to 80xc2x0 C., or alternatively by reaction with a peracid such as peracetic acid or 3-chloroperoxybenzoic acid in a solvent, e.g. dichloromethane, at ambient temperature.
Where salts of compounds of formula (1) are desired, these may be prepared by conventional means, for example by reaction of a compound of formula (1) with an appropriate acid or base in a suitable solvent or mixture of solvents, e.g. an organic solvent such as an ether, e.g. diethylether, or an alcohol, e.g. ethanol.